胃癌相关肿瘤标志物：从早期诊断到疗效预测、治疗选择指导

摘要/Abstract

摘要： 世界范围内，胃癌发病广泛，侵袭性强，5年生存率低。但胃癌的生物学行为和遗传学性质都不明确，分子生物学水平上的致癌机制尚不清楚。虽然近年来胃癌发病率有下降趋势，但患者生存率仍不理想。因此，采取措施早期筛查、早诊断，选择合适的治疗方案进行早治疗，选取合适的检测手段进行有效监测随访，可以提高早诊率，改善预后，预测复发，评估治疗反应。生物标志物的检测指标可以量化，检测结果客观，可以用于反映生理机能、病理表现以及预测药物疗效，甚至可以用于指导用药。DNA、RNA、蛋白、外泌体等目前成为生物标志物的研究重点。鉴于此，本研究全面总结胃癌相关生物标志物在诊断、疗效预测、复发监测及随访等领域的研究进展，对胃癌中生物标志物的研究方向进行分类，综述各分类潜在有价值的候选分子或标本，探寻可能用于临床的标志物，以期为实现肿瘤的个体化治疗提供参考借鉴。

关键词: font-size:medium, ">生物标志物；胃癌；诊断；预后；疗效预测

Abstract: The morbidity and mortality of gastric cancer is high in the world. Gastric cancer is aggressive and invasive disease with a low 5-year survival rate. However， the biological behavior and genetic characteristics of gastric cancer are still ambiguous， and the carcinogenic mechanism at the molecular biological level is still not clear. Although the incidence of gastric cancer has decreased in recent years， the survival rate remains unsatisfactory. Therefore， measures should be taken for screening and early detection， appropriate treatment strategy should be taken for early treatment，suitable imaging and laboratory test should be selected for monitoring and follow-up，so as to increase the rate of early diagnosis，improve prognosis， predict relapse and evaluate therapeutic response. The detection indexes of biomarkers can be quantified， and the detection results can be used to reflect the physiological function， pathological performance and predict the efficacy of drugs， and even to guide drug use. DNA， RNA， protein and exosomes have become the research focus of biomarkers. In view of this，this study summarized current progress on gastric cancer related biomarker in the fields of diagnosis， efficacy prediction， recurrence monitoring and follow-up. Meanwhile， the research directions of biomarkers of gastric cancer ware classified， the potential valuable candidate molecules or specimens of each classification were summarized， and the potential biomarkers for clinical application were investigated， so as to provide reference for the realization of individualized treatment of gastric cancer.

Key words: font-size:medium, ">Biomarkers； Gastric cancer； Diagnosis； Prognosis； Efficacy prediction

中图分类号:

单鹄声, 孟亮亮, 肖越勇. 胃癌相关肿瘤标志物：从早期诊断到疗效预测、治疗选择指导[J]. 中国医药导刊, 2023, 25(4): 375-388.

SHAN Husheng, MENG Liangliang, XIAO Yueyong. Gastric Cancer Related Tumor Markers： from Early Diagnosis to Efficacy Prediction and Treatment Selection[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2023, 25(4): 375-388.

参考文献

[1]Sung H， Ferlay J， Siegel RL， et al. Global cancer statistics 2020： Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin， 2021，71(3)：209-249.
     [2]Smyth EC， Nilsson M， Grabsch HI， et al. Gastric cancer [J]. Lancet， 2020，396(10251)：635-648.
     [3]Wu D， Zhang P， Ma J， et al. Serum biomarker panels for the diagnosis of gastric cancer [J]. Cancer Med， 2019，8(4)：1576-1583.
     [4]Feng F， Tian Y， Xu G， et al. Diagnostic and prognostic value of cea， ca19-9， afp and ca125 for early gastric cancer [J]. BMC Cancer， 2017，17(1)：737-743.
     [5]Culcu S， Yuksel C， Aydin F， et al. The effect of cea/albumin ratio in gastric cancer patient on prognostic factors [J]. Ann Ital Chir， 2022，93：447-452.
     [6]Moriyama J， Oshima Y， Nanami T， et al. Prognostic impact of cea/ca19-9 at the time of recurrence in patients with gastric cancer [J]. Surg Today， 2021，51(10)：1638-1648.
     [7]Shimada H， Noie T， Ohashi M， et al. Clinical significance of serum tumor markers for gastric cancer： a systematic review of literature by the task force of the japanese gastric cancer association [J]. Gastric Cancer， 2014，17(1)：26-33.
     [8]Asao T， Fukuda T， Yazawa S， et al. Carcinoembryonic antigen levels in peritoneal washings can predict peritoneal recurrence after curative resection of gastric cancer [J]. Cancer， 1991，68(1)：44-47.
     [9]Takebayashi K， Murata S， Kodama H， et al. Long-term prognosis of patients with cancer-related genes detected in postoperative peritoneal washings obtained during curative gastrectomy [J]. Eur J Surg Oncol， 2022，48(1)：177-182.
     [10]Han ES， Lee HH， Lee JS， et al. At which stage of gastric cancer progression do levels of carcinoembryonic antigen and carbohydrate antigen 19-9 increase? Application in advanced gastric cancer treatment [J]. J Gastric Cancer， 2014，14(2)：123-128.
     [11]Shibata C， Nakano T， Yasumoto A， et al. Comparison of CEA and CA19-9 as a predictive factor for recurrence after curative gastrectomy in gastric cancer [J]. BMC Surg， 2022，22(1)：213-220.
     [12]Song YX， Huang XZ， Gao P， et al. Clinicopathologic and prognostic value of serum carbohydrate antigen 19-9 in gastric cancer： a meta-analysis [J]. Dis Markers， 2015，2015：549843-549854.
     [13]Shen M， Wang H， Wei K， et al. Five common tumor biomarkers and cea for diagnosing early gastric cancer： a protocol for a network meta-analysis of diagnostic test accuracy [J]. Medicine (Baltimore)， 2018，97(19)：e0577-e0581.
     [14]Li M， Zheng G， Yu L， et al. Diagnostic value of mri-dwi signal intensity value combined with serum pgi， pgii and ca199 in early gastric cancer [J]. Cell Mol Biol (Noisy-le-grand)， 2021，67(2)：95-100.
     [15]Zhu Y， Zhao W， Mao G. Perioperative lymphocyte-to-monocyte ratio changes plus ca199 in predicting the prognosis of patients with gastric cancer [J]. J Gastrointest Oncol， 2022，13(3)：1007-1021.
     [16]He B， Zhang HQ， Xiong SP， et al. Changing patterns of serum cea and ca199 for evaluating the response to first-line chemotherapy in patients with advanced gastric adenocarcinoma [J]. Asian Pac J Cancer Prev， 2015，16(8)：3111-3116.
     [17]Joshi SS， Badgwell BD. Current treatment and recent progress in gastric cancer [J]. CA Cancer J Clin， 2021，71(3)：264-279.
     [18]Bang YJ， Van Cutsem E， Feyereislova A， et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of her2-positive advanced gastric or gastro-oesophageal junction cancer (toga)： a phase 3， open-label， randomised controlled trial [J]. Lancet， 2010，376(9742)：687-697.
     [19]Yoshida H， Yamamoto N， Taniguchi H， et al. Comparison of her2 status between surgically resected specimens and matched biopsy specimens of gastric intestinal-type adenocarcinoma [J]. Virchows Arch， 2014，465(2)：145-154.
     [20]Bozzetti C， Negri FV， Lagrasta CA， et al. Comparison of her2 status in primary and paired metastatic sites of gastric carcinoma [J]. Br J Cancer， 2011，104(9)：1372-1376.
     [21]Nergiz D， Alikano gˇlu AS， Süren D， et al. Concordance of her2 status tested by ihc and fish in biopsy and surgical resection specimens and comparison with clinicopathological features in gastric carcinoma [J]. Indian J Pathol Microbiol， 2022，65(2)：321-327.
     [22]Ciesielski M， Szajewski M， Walczak J， et al. Impact of chromosome 17 centromere copy number increase on patient survival and human epidermal growth factor receptor 2 expression in gastric adenocarcinoma [J]. Oncol Lett， 2021，21(2)：142-150.
     [23]Liang H， Li Z， Huang Z， et al. Prognostic characteristics and clinical response to immunotherapy targeting programmed cell death 1 for patients with advanced gastric cancer with liver metastases [J]. Front Immunol， 2022，13：1015549-1015562.
     [24]Shu S， Yamashita-Kashima Y， Yanagisawa M， et al. Trastuzumab in combination with paclitaxel enhances antitumor activity by promoting apoptosis in human epidermal growth factor receptor 2-positive trastuzumab-resistant gastric cancer xenograft models [J]. Anticancer Drugs， 2020，31(3)：241-250.
     [25]Oyama K， Fushida S， Tsukada T， et al. Evaluation of serum her2-ecd levels in patients with gastric cancer [J]. J Gastroenterol， 2015，50(1)：41-45.
     [26]Díaz-Serrano A， Angulo B， Dominguez C， et al. Genomic profiling of her2-positive gastric cancer： Pi3k/akt/mtor pathway as predictor of outcomes in her2-positive advanced gastric cancer treated with trastuzumab [J]. Oncologist， 2018，23(9)：1092-1102.
     [27]Kim ST， Banks KC， Pectasides E， et al. Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during her2 therapy in her2+ gastric cancer patients [J]. Ann Oncol， 2018，29(4)：1037-1048.
     [28]Xu Y， Zhang P， Zhang K， et al. The application of ca72-4 in the diagnosis， prognosis， and treatment of gastric cancer [J]. Biochim Biophys Acta Rev Cancer， 2021，1876(2)：188634.
     [29]Hirajima S， Komatsu S， Ichikawa D， et al. Liver metastasis is the only independent prognostic factor in afp-producing gastric cancer [J]. World J Gastroenterol， 2013，19(36)：6055-6061.
     [30]Lu J， Ding Y， Chen Y， et al. Whole-exome sequencing of alpha-fetoprotein producing gastric carcinoma reveals genomic profile and therapeutic targets [J]. Nat Commun， 2021，12(1)：3946-3959.
     [31]Kong XX， Li XL， Tian Y， et al. The clinicopathological characteristics of alpha-fetoprotein-producing adenocarcinoma of the gastrointestinal tract-a single-center retrospective study [J]. Front Oncol， 2021，11：635537-635549.
     [32]Luo T， Chen W， Wang L， et al. Ca125 is a potential biomarker to predict surgically incurable gastric and cardia cancer： a retrospective study [J]. Medicine (Baltimore)， 2016，95(51)：e5297-e5306.
     [33]Lin X， Han T， Zhuo M， et al. A retrospective study of clinicopathological characteristics and prognostic factors of krukenberg tumor with gastric origin [J]. J Gastrointest Oncol， 2022，13(3)：1022-1034.
     [34]Namikawa T， Kawanishi Y， Fujisawa K， et al. Serum carbohydrate antigen 125 is a significant prognostic marker in patients with unresectable advanced or recurrent gastric cancer [J]. Surg Today， 2018，48(4)：388-394.
     [35]Babina IS， Turner NC. Advances and challenges in targeting fgfr signalling in cancer [J]. Nat Rev Cancer， 2017，17(5)：318-332.
     [36]Nagatsuma AK， Aizawa M， Kuwata T， et al. Expression profiles of her2， egfr， met and fgfr2 in a large cohort of patients with gastric adenocarcinoma [J]. Gastric Cancer， 2015，18(2)：227-238.
     [37]Fuse N， Kuboki Y， Kuwata T， et al. Prognostic impact of her2， egfr， and c-met status on overall survival of advanced gastric cancer patients [J]. Gastric Cancer， 2016，19(1)：183-191.
     [38]Jogo T， Nakamura Y， Shitara K， et al. Circulating tumor DNA analysis detects fgfr2 amplification and concurrent genomic alterations associated with fgfr inhibitor efficacy in advanced gastric cancer [J]. Clin Cancer Res， 2021，27(20)：5619-5627.
     [39]Hosoda K， Yamashita K， Ushiku H， et al. Prognostic relevance of fgfr2 expression in stage ii/iii gastric cancer with curative resection and s-1 chemotherapy [J]. Oncol Lett， 2018，15(2)：1853-1860.
     [40]Dhakras P， Uboha N， Horner V， et al. Gastrointestinal cancers： current biomarkers in esophageal and gastric adenocarcinoma [J]. Transl Gastroenterol Hepatol， 2020，5：55-68.
     [41]Panarese I， De Vita F， Ronchi A， et al. Predictive biomarkers along gastric cancer pathogenetic pathways [J]. Expert Rev Anticancer Ther， 2017，17(5)：417-425.
     [42]Wang Y， Shi T， Wang X， et al. Fgfr2 alteration as a potential therapeutic target in poorly cohesive gastric carcinoma [J]. J Transl Med， 2021，19(1)：401-422.
     [43]Meric-Bernstam F， Bahleda R， Hierro C， et al. Futibatinib， an irreversible fgfr1-4 inhibitor， in patients with advanced solid tumors harboring fgf/fgfr aberrations： a phase i dose-expansion study [J]. Cancer Discov， 2022，12(2)：402-415.
     [44]Im S， Cho YK， Kang D， et al. Combined high nedd9 expression and e-cadherin loss correlate with poor clinical outcome in gastric cancer [J]. J Gastroenterol Hepatol， 2022，37(12)：2255-2263.
     [45]Carneiro P， Fernandes MS， Figueiredo J， et al. E-cadherin dysfunction in gastric cancer--cellular consequences， clinical applications and open questions [J]. FEBS Lett， 2012，586(18)：2981-2989.
     [46]Gamble LA， Heller T， Davis JL. Hereditary diffuse gastric cancer syndrome and the role of cdh1： a review [J]. JAMA Surg， 2021，156(4)：387-392.
     [47]Ferraz MA， Zabaglia LM， Pereira WN， et al. Downregulated expression of e-cadherin and tp53 in patients with gastric diseases： the involvement of h. Pylori infection and its virulence markers [J]. J Gastrointest Cancer， 2016，47(1)：20-26.
     [48]Carneiro F. Familial and hereditary gastric cancer， an overview [J]. Best Pract Res Clin Gastroenterol， 2022，58-59：101800-101816.
     [49]Hu MN， Hu SH， Zhang XW， et al. Overview on new progress of hereditary diffuse gastric cancer with cdh1 variants [J]. Tumori， 2020，106(5)：346-355.
     [50]Liu X， Chu KM. E-cadherin and gastric cancer： cause， consequence， and applications [J]. Biomed Res Int， 2014：637308-637317.
     [51]Taja-Chayeb L， Vidal-Millán S， Trejo-Becerril C， et al. Hereditary diffuse gastric cancer (hdgc). an overview [J]. Clin Res Hepatol Gastroenterol， 2022，46(4)：101820-101829.
     [52]Hanahan D. Hallmarks of cancer： new dimensions [J]. Cancer Discov， 2022，12(1)：31-46.
     [53]Saintigny P， Mitani Y， Pytynia KB， et al. Frequent pten loss and differential her2/pi3k signaling pathway alterations in salivary duct carcinoma： implications for targeted therapy [J]. Cancer， 2018，124(18)：3693-3705.
     [54]Fattahi S， Amjadi-Moheb F， Tabaripour R， et al. Pi3k/akt/mtor signaling in gastric cancer： epigenetics and beyond [J]. Life Sci， 2020，262：118513-118526.
     [55]Matsuoka T， Yashiro M. The role of pi3k/akt/mtor signaling in gastric carcinoma [J]. Cancers (Basel)， 2014，6(3)：1441-1463.
     [56]Baghery Saghchy Khorasani A， Pourbagheri-Sigaroodi A， Pirsalehi A， et al.The pi3k/akt/mtor signaling pathway in gastric cancer； from oncogenic variations to the possibilities for pharmacologic interventions [J]. Eur J Pharmacol， 2021，898：173983-173999.
     [57]Yang J， Liu Z， Zeng B， et al. Epstein-barr virus-associated gastric cancer： A distinct subtype [J]. Cancer Lett， 2020，495：191-199.
     [58]Ribeiro J， Oliveira A， Malta M， et al. Clinical and pathological characterization of epstein-barr virus-associated gastric carcinomas in portugal [J]. World J Gastroenterol， 2017，23(40)：7292-7302.
     [59]Ito C， Nishizuka SS， Ishida K， et al. Analysis of pik3ca mutations and pi3k pathway proteins in advanced gastric cancer [J]. J Surg Res， 2017，212：195-204.
     [60]Ji J， Wang Z， Sun W， et al. Effects of cynaroside on cell proliferation， apoptosis， migration and invasion though the met/akt/mtor axis in gastric cancer [J]. Int J Mol Sci， 2021，22(22)：12125-12139.
     [61]Chen L， Shi Y， Zhu X， et al. IL-10 secreted by cancer-associated macrophages regulates proliferation and invasion in gastric cancer cells via c-met/stat3 signaling [J]. Oncol Rep， 2019，42(2)：595-604.
     [62]Kim HS， Chon HJ， Kim H， et al. Met in gastric cancer with liver metastasis： The relationship between met amplification and met overexpression in primary stomach tumors and liver metastasis [J]. J Surg Oncol， 2018，117(8)：1679-1686.
     [63]Peng J, Qi S, Wang P, et al. Diagnosis and prognostic significance of c-Met in cervical cancer: a Meta-analysis[J]. Dis Markers, 2016, 2016:6594016-6594025.
     [64]Pereira MA, Ramos M, Dias AR, et al. RhoA, claudin 18, and c-MET in gastric cancer: clinicopathological characteristics and prognostic significance in curative resected patients[J]. Med Sci (Basel), 2021, 10: 1-17.
     [65]Lee J， Kim ST， Kim K， et al. Tumor genomic profiling guides patients with metastatic gastric cancer to targeted treatment： the viktory umbrella trial [J]. Cancer Discov， 2019，9(10)：1388-1405.
     [66]Noguchi E， Saito N， Kobayashi M， et al. Clinical significance of hepatocyte growth factor/c-met expression in the assessment of gastric cancer progression [J]. Mol Med Rep， 2015，11(5)：3423-3431.
     [67]Yashiro M, Nishii T, Hasegawa T, et al. A c-Met inhibitor increases the chemosensitivity of cancer stem cells to the irinotecan in gastric carcinoma[J]. Br J Cancer, 2013, 109:2619-2628.
     [68]Takahashi N， Furuta K， Taniguchi H， et al. Serum level of hepatocyte growth factor is a novel marker of predicting the outcome and resistance to the treatment with trastuzumab in her2-positive patients with metastatic gastric cancer [J]. Oncotarget， 2016，7(4)：4925-4938.
     [69]Haque E， Esmail A， Muhsen I， et al. Recent trends and advancements in the diagnosis and management of gastric cancer [J]. Cancers (Basel)， 2022，14(22)：5615-5642.
     [70]Ajani JA， D′Amico TA， Bentrem DJ， et al. Gastric cancer， version 2.2022， nccn clinical practice guidelines in oncology [J]. J Natl Compr Canc Netw， 2022，20(2)：167-192.
     [71]Fuchs CS， Tomasek J， Yong CJ， et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (regard)： an international， randomised， multicentre， placebo-controlled， phase 3 trial [J]. Lancet， 2014，383(9911)：31-39.
     [72]Wilke H， Muro K， Van Cutsem E， et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (rainbow)： a double-blind， randomised phase 3 trial [J]. Lancet Oncol， 2014，15(11)：1224-1235.
     [73]Tabernero J， Hozak RR， Yoshino T， et al. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from raise， a global， randomized， double-blind， phase iii study [J]. Ann Oncol， 2018，29(3)：602-609.
     [74]Fuchs CS, Shitara K, Di Bartolomeo M, et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2019, 20:420-435.
     [75]Fuchs CS， Doi T， Jang RW， et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer： phase 2 clinical keynote-059 trial [J]. JAMA Oncol， 2018，4(5)：e180013.
     [76]Catenacci DVT， Tebbutt NC， Davidenko I， et al. Rilotumumab plus epirubicin， cisplatin， and capecitabine as first-line therapy in advanced met-positive gastric or gastro-oesophageal junction cancer (rilomet-1)： a randomised， double-blind， placebo-controlled， phase 3 trial [J]. Lancet Oncol， 2017，18(11)：1467-1482.
     [77]Li F， Li S， Wang X， et al. To investigate the prognostic factors of stage ⅰ-ⅱ gastric cancer based on p53 mutation and tumor budding [J]. Pathol Res Pract， 2022，240：154195-154203.
     [78]Battista S， Ambrosio MR， Limarzi F， et al. Molecular alterations in gastric preneoplastic lesions and early gastric cancer [J]. Int J Mol Sci， 2021，22(13)：6652.
     [79]Jang H， Seo AN， Kim M. Clinicopathological characteristics of advanced epstein-barr virus-associated gastric cancer highlighting aberrant p53 expression [J]. Anticancer Res， 2022，42(10)：4955-4962.
     [80]Francisco G， Menezes PR， Eluf-Neto J， et al. Arg72pro tp53 polymorphism and cancer susceptibility： a comprehensive meta-analysis of 302 case-control studies [J]. Int J Cancer， 2011，129(4)：920-930.
     [81]Pauken KE， Torchia JA， Chaudhri A， et al. Emerging concepts in pd-1 checkpoint biology [J]. Semin Immunol， 2021，52：101480-1014517.
     [82]Yoshida T， Ogura G， Tanabe M， et al. Clinicopathological features of pd-l1 protein expression， ebv positivity， and msi status in patients with advanced gastric and esophagogastric junction adenocarcinoma in japan [J]. Cancer Biol Ther， 2022，23(1)：191-200.
     [83]Bang YJ， Kang YK， Catenacci DV， et al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma： results from the phase ii nonrandomized keynote-059 study [J]. Gastric Cancer， 2019，22(4)：828-837.
     [84]Tabernero J， Bang YJ， Van Cutsem E， et al. Keynote-859： a phase Ⅲ study of pembrolizumab plus chemotherapy in gastric/gastroesophageal junction adenocarcinoma [J]. Future Oncol， 2021，17(22)：2847-2855.
     [85]Hu M， Polyak K. Serial analysis of gene expression [J]. Nature Protocols， 2006，1(4)：1743-1760.
     [86]Ojetti V， Persiani R， Cananzi FC， et al. Cdna-microarray analysis as a new tool to predict lymph node metastasis in gastric cancer [J]. World J Surg， 2014，38(8)：2058-2064.
     [87]Wang H， Ding Y， Chen Y， et al. A novel genomic classification system of gastric cancer via integrating multidimensional genomic characteristics [J]. Gastric Cancer， 2021，24(6)：1227-1241.
     [88]Pinto M， Oliveira C， Machado JC， et al. Msi-l gastric carcinomas share the hmlh1 methylation status of msi-h carcinomas but not their clinicopathological profile [J]. Lab Invest， 2000，80(12)：1915-1923.
     [89]Yoon K， Lee S， Han TS， et al. Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in korean gastric cancers [J]. Genome Res， 2013，23(7)：1109-1117.
     [90]Puliga E， Corso S， Pietrantonio F， et al. Microsatellite instability in gastric cancer： Between lights and shadows [J]. Cancer Treat Rev， 2021，95：102175-102185.
     [91]Smyth EC， Wotherspoon A， Peckitt C， et al. Mismatch repair deficiency， microsatellite instability， and survival： an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (magic) trial [J]. JAMA Oncol， 2017，3(9)：1197-1203.
     [92]Qu Y， Dang S， Hou P. Gene methylation in gastric cancer [J]. Clin Chim Acta， 2013，424：53-65.
     [93]Ding Y， Lian HF， Du Y. Clinicopathological significance of chfr promoter methylation in gastric cancer： a meta-analysis [J]. Oncotarget， 2018，9(11)：10083-10090.
     [94]Drici Ael M， Moulessehoul S， Tifrit A， et al. Effect of il-1β and il-1rn polymorphisms in carcinogenesis of the gastric mucosa in patients infected with helicobacter pylori in algeria [J]. Libyan J Med， 2016，11:31576-31583.
     [95]Suenaga M， Yamada S， Fuchs BC， et al. Cd44 single nucleotide polymorphism and isoform switching may predict gastric cancer recurrence [J]. J Surg Oncol， 2015，112(6)：622-628.
     [96]Kumar V， Ramnarayanan K， Sundar R， et al. Single-cell atlas of lineage states， tumor microenvironment， and subtype-specific expression programs in gastric cancer [J]. Cancer Discov， 2022，12(3)：670-691.
     [97]Siravegna G， Marsoni S， Siena S， et al. Integrating liquid biopsies into the management of cancer [J]. Nat Rev Clin Oncol， 2017，14(9)：531-548.
     [98]Castro-Giner F， Aceto N. Tracking cancer progression： from circulating tumor cells to metastasis [J]. Genome Med， 2020，12(1)：31-43.
     [99]Lengyel CG， Hussain S， Trapani D， et al. The emerging role of liquid biopsy in gastric cancer [J]. J Clin Med， 2021，10(10)：2108-2124.
     [100]Jelski W， Mroczko B. Molecular and circulating biomarkers of gastric cancer [J]. Int J Mol Sci， 2022，23(14)：7588-7601.
     [101]Huang X， Gao P， Sun J， et al. Clinicopathological and prognostic significance of circulating tumor cells in patients with gastric cancer： a meta-analysis [J]. Int J Cancer， 2015，136(1)：21-33.
     [102]Zhang Q， Shan F， Li Z， et al. A prospective study on the changes and clinical significance of pre-operative and post-operative circulating tumor cells in resectable gastric cancer [J]. J Transl Med， 2018，16(1)：171-183.
     [103]Szczepanik A， Sierzega M， Drabik G， et al. Cd44(+) cytokeratin-positive tumor cells in blood and bone marrow are associated with poor prognosis of patients with gastric cancer [J]. Gastric Cancer， 2019，22(2)：264-272.
     [104]Yi-Wen W， Long-Long L， Ming L， et al. Stem cell-like circulating tumor cells indicate poor prognosis in gastric cancer [J]. Arch Med Sci， 2022，18(5)：1297-1307.
     [105]Mishima Y， Matsusaka S， Chin K， et al. Detection of her2 amplification in circulating tumor cells of her2-negative gastric cancer patients [J]. Target Oncol， 2017，12(3)：341-351.
     [106]Umer M， Vaidyanathan R， Nguyen NT， et al. Circulating tumor microemboli： Progress in molecular understanding and enrichment technologies [J]. Biotechnol Adv， 2018，36(4)：1367-1389.
     [107]Abdallah EA， Braun AC， Flores B， et al.The potential clinical implications of circulating tumor cells and circulating tumor microemboli in gastric cancer [J]. Oncologist， 2019，24(9)：e854-e863.
     [108]Martignano F. Cell-free DNA： an overview of sample types and isolation procedures [J]. Methods Mol Biol， 2019，1909：13-27.
     [109]Qi Q， Pan YF， Shen JJ， et al. Circulating DNA for detection of gastric cancer [J]. Eur Rev Med Pharmacol Sci， 2016，20(12)：2558-2564.
     [110]Campos-Carrillo A， Weitzel JN， Sahoo P， et al. Circulating tumor DNA as an early cancer detection tool [J]. Pharmacol Ther， 2020，207：107458-107474.
     [111]Liu MC， Oxnard GR， Klein EA， et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA [J]. Ann Oncol， 2020，31(6)：745-759.
     [112]Gao Y， Zhang K， Xi H， et al. Diagnostic and prognostic value of circulating tumor DNA in gastric cancer： a meta-analysis [J]. Oncotarget， 2017，8(4)：6330-6340.
     [113]Balgkouranidou I， Karayiannakis A， Matthaios D， et al. Assessment of sox17 DNA methylation in cell free DNA from patients with operable gastric cancer. association with prognostic variables and survival [J]. Clin Chem Lab Med， 2013，51(7)：1505-1510.
     [114]Balgkouranidou I， Matthaios D， Karayiannakis A， et al. Prognostic role of apc and rassf1a promoter methylation status in cell free circulating DNA of operable gastric cancer patients [J]. Mutat Res， 2015，778：46-51.
     [115]Kim ST， Cristescu R， Bass AJ， et al. Comprehensive molecular characterization of clinical responses to pd-1 inhibition in metastatic gastric cancer [J]. Nat Med， 2018，24(9)：1449-1458.
     [116]Tian S， Peng P， Li J， et al. Serpinh1 regulates emt and gastric cancer metastasis via the wnt/β-catenin signaling pathway [J]. Aging (Albany NY)， 2020，12(4)：3574-3593.
     [117]Wu HH， Lin WC， Tsai KW. Advances in molecular biomarkers for gastric cancer： mirnas as emerging novel cancer markers [J]. Expert Rev Mol Med， 2014，16：e1-18.
     [118]Tavakoli F， Khatami SS， Momeni F， et al. Gastric cancer diagnosis： from imaging techniques to biochemical biomarkers [J]. Curr Mol Med， 2021，21(5)：355-375.
     [119]Mitchell PS， Parkin RK， Kroh EM， et al. Circulating micrornas as stable blood-based markers for cancer detection [J]. Proc Natl Acad Sci USA， 2008，105(30)：10513-10518.
     [120]Sierzega M， Kaczor M， Kolodziejczyk P， et al. Evaluation of serum microrna biomarkers for gastric cancer based on blood and tissue pools profiling： the importance of mir-21 and mir-331 [J]. Br J Cancer， 2017，117(2)：266-273.
     [121]Zhang Y， Guan DH， Bi RX， et al. Prognostic value of micrornas in gastric cancer： a meta-analysis [J]. Oncotarget， 2017，8(33)：55489-55510.
     [122]Shoda K， Ichikawa D， Fujita Y， et al. Clinical utility of circulating cell-free epstein-barr virus DNA in patients with gastric cancer [J]. Oncotarget， 2017，8(17)：28796-28804.
     [123]Zhang Y， Wang M， Zang X， et al. Circhn1 affects cell proliferation and migration in gastric cancer [J]. J Clin Lab Anal， 2020，34(10)：e23433-e23442.
     [124]Zhang Y， Jiang J， Zhang J， et al. Circdido1 inhibits gastric cancer progression by encoding a novel dido1-529aa protein and regulating prdx2 protein stability [J]. Mol Cancer， 2021，20(1)：101-118.
     [125]Xie M， Yu T， Jing X， et al. Exosomal circshkbp1 promotes gastric cancer progression via regulating the mir-582-3p/hur/vegf axis and suppressing hsp90 degradation [J]. Mol Cancer， 2020，19(1)：112-134.
     [126]Zhang X， Wang S， Wang H， et al. Circular rna circnrip1 acts as a microrna-149-5p sponge to promote gastric cancer progression via the akt1/mtor pathway [J]. Mol Cancer， 2019，18(1)：20-44.
     [127]Chen DL， Sheng H， Zhang DS， et al. The circular rna circdlg1 promotes gastric cancer progression and anti-pd-1 resistance through the regulation of cxcl12 by sponging mir-141-3p [J]. Mol Cancer， 2021，20(1)：166-184.
     [128]Valadi H， Ekstrm K， Bossios A， et al. Exosome-mediated transfer of mrnas and micrornas is a novel mechanism of genetic exchange between cells [J]. Nat Cell Biol， 2007，9(6)：654-659.
     [129]Kalluri R， LeBleu VS.The biology， function， and biomedical applications of exosomes [J]. Science， 2020，6478：367-407.
     [130]Wang N， Wang L， Yang Y， et al. A serum exosomal microrna panel as a potential biomarker test for gastric cancer [J]. Biochem Biophys Res Commun， 2017，493(3)：1322-1328.
     [131]Tokuhisa M， Ichikawa Y， Kosaka N， et al. Exosomal mirnas from peritoneum lavage fluid as potential prognostic biomarkers of peritoneal metastasis in gastric cancer [J]. PLoS One， 2015，10(7)：e0130472-e0130485.
     [132]Watanabe Y， Kim HS， Castoro RJ， et al. Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes [J]. Gastroenterology， 2009，136(7)：2149-2158.
     [133]Yamamoto H， Watanabe Y， Oikawa R， et al. Barhl2 methylation using gastric wash DNA or gastric juice exosomal DNA is a useful marker for early detection of gastric cancer in an h. pylori-independent manner [J]. Clin Transl Gastroenterol， 2016，7(7)：e184-185.
     [134]Virgilio E， Giarnieri E， Giovagnoli MR， et al. Gastric juice micrornas as potential biomarkers for screening gastric cancer： a systematic review [J]. Anticancer Res， 2018，38(2)：613-616.
     [135]Parsonnet J， Friedman GD， Vandersteen DP， et al. Helicobacter pylori infection and the risk of gastric carcinoma [J]. N Engl J Med， 1991，325(16)：1127-1131.
     [136]Hatakeyama M. Structure and function of helicobacter pylori caga， the first-identified bacterial protein involved in human cancer [J]. Proc Jpn Acad Ser B Phys Biol Sci， 2017，93(4)：196-219.
     [137]Saju P， Murata-Kamiya N， Hayashi T， et al. Host shp1 phosphatase antagonizes helicobacter pylori caga and can be downregulated by epstein-barr virus [J]. Nat Microbiol， 2016，1：16026-16034.
     [138]Ferreira RM， Machado JC， Figueiredo C. Clinical relevance of helicobacter pylori vaca and caga genotypes in gastric carcinoma [J]. Best Pract Res Clin Gastroenterol， 2014，28(6)：1003-1015.
     [139]Yu S， Meng H， Shi S， et al. Mir-548d-3p inhibits the invasion and migration of gastric cancer cells by targeting gkn1 [J]. J Clin Lab Anal， 2022，36(7)：e24520.
     [140]Suh YS， Na D， Lee JS， et al. Comprehensive molecular characterization of adenocarcinoma of the gastroesophageal junction between esophageal and gastric adenocarcinomas [J]. Ann Surg， 2022，275(4)：706-717.

快速检索引用检索图表检索高级检索